We thank Watkins and Hutchinson for their thoughtful letter regarding our Opinion article on human microglia and understand the concerns and cautions that they have raised. However, in our Opinion article we focus on the study of adult human microglia in various human brain neuropathologies from post-mortem and biopsy brain tissue. We believe that early developmental stage microglia, whatever the species, are less likely to be good models for adult microglia in aged human brain (in which most neurodegenerative disorders manifest). By directly studying microglia in the diseased adult human brain, the disease context can be studied and the information garnered used to help validate animal models of these diseases and inform researchers in developing newer models.However, we do appreciate that there will be marked differences in brain tissue derived from adult humans; post-mortem/post-surgery delay times, genetic background, medication use, disease, diet, and many other variables cannot be controlled. This is much more varied than the controlled conditions routinely performed in animal studies, thus making comparisons difficult. Although we agree that this means differences in studies using human versus animal microglia might be due to factors other than species, including experimental procedures, it is ultimately humans that we wish to understand. The inherent variability of human cells and tissue is likely to be more representative of the human populations for which treatments will be used.Although there are many studies that are well informed by human data, we do appreciate that for many researchers these human-based techniques may not be feasible. Although we believe that research has intrinsic value even if it does not impact directly on understanding the human brain, we would suggest that some human-based validation be performed, either directly or by others studying the same research questions. In particular, this would be very helpful for studies aimed at developing disease-modifying treatments for neurodegenerative disorders.To study the human brain, neuroscientists have developed close links with their clinical colleagues and with community support organizations and human brain banks. We would encourage more neuroscientists to form these enriching links to develop and extend, in their own laboratories, this expertise in using adult human brain tissue and cells for studying microglial biology and brain disorders. Ultimately, as with animal models, we will know whether this human approach is valid only if and when treatments developed are effective in treating people with neurodegenerative disorders. It is our belief that both approaches, animal and human, working in unison hold the best hope for understanding and treating human brain disorders.

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对沃特金斯和哈钦森的回应

我们感谢沃特金斯和哈钦森对我们关于人类小胶质细胞的意见文章的深思熟虑，并理解他们提出的担忧和警告。然而，在我们的意见文章中，我们专注于研究来自死后和活检脑组织的各种人脑神经病理学中的成人小胶质细胞。我们认为，早期发育阶段的小胶质细胞，无论是什么物种，都不太可能成为老年人类大脑（大多数神经退行性疾病在其中表现）中成年小胶质细胞的良好模型。通过直接研究患病成人大脑中的小胶质细胞，可以研究疾病背景，并将收集到的信息用于帮助验证这些疾病的动物模型，并为研究人员开发新模型提供信息。然而，我们确实意识到成年人的脑组织会有显着差异；验尸/手术后延迟时间、遗传背景、药物使用、疾病、饮食和许多其他变量无法控制。这比在动物研究中常规进行的受控条件要多样化得多，因此难以进行比较。尽管我们同意这意味着使用人类与动物小胶质细胞的研究的差异可能是由于物种以外的因素造成的，包括实验程序，但最终我们希望了解的是人类。人体细胞和组织的固有变异性可能更能代表将使用治疗的人群。 尽管有许多研究充分利用了人类数据，我们确实意识到，对于许多研究人员来说，这些基于人类的技术可能不可行。尽管我们相信研究具有内在价值，即使它不会直接影响对人类大脑的理解，但我们建议直接或由其他研究相同研究问题的人进行一些基于人类的验证。特别是，这对于旨在开发神经退行性疾病的疾病改善疗法的研究非常有帮助。为了研究人脑，神经科学家与他们的临床同事、社区支持组织和人脑库建立了密切的联系。我们将鼓励更多的神经科学家建立这些丰富的联系，在他们自己的实验室中开发和扩展，这种使用成人脑组织和细胞研究小胶质细胞生物学和脑部疾病的专业知识。最终，与动物模型一样，只有当开发的治疗方法对治疗神经退行性疾病患者有效时，我们才会知道这种人类方法是否有效。我们相信，动物和人类协同工作的方法最有希望理解和治疗人类大脑疾病。